Exercise, especially endurance exercise, is known to have beneficial effects on brain health and cognitive function (Cotman et al. (2007) Trends Neurosci. 30, 464-472 and Mattson (2012) Cell Metab. 16, 706-722). This improvement in cognitive function with exercise has been most prominently observed in the aging population (Colcombe and Kramer (2003) Psych Sci. 14, 125-130). Exercise has also been reported to ameliorate outcomes in neurological diseases like depression, epilepsy, stroke, Alzheimer's and Parkinson's Disease (Ahlskog (2011) Neurology 77, 288-294; Arida et al. (2008) Sports Med. (Auckland, NZ) 38, 607-615; Buchman et al. (2012) Neurology 78, 1323-1329; Russo-Neustadt et al. (1999) Neuropsychopharm. 21, 679-682; and Zhang et al. (2012) Neuroscience 205, 10-17). The effects of exercise on the brain are most apparent in the hippocampus and its dentate gyrus, a part of the brain involved in learning and memory. Specific beneficial effects of exercise in the brain have been reported to include increases in the size of and blood flow to the hippocampus in humans and morphological changes in dendrites and dendritic spines, increased synapse plasticity and, importantly, de novo neurogenesis in the dentate gyrus in various mouse models of exercise (Cotman et al. (2007) Trends Neurosci. 30, 464-472 and Mattson (2012) Cell Metab. 16, 706-722). De novo neurogenesis in the adult brain occurs is observed in only two areas; the dentate gyrus of the hippocampus is one of them and exercise is one of the few known stimuli of this de novo neurogenesis (Kobilo et al. (2011) Learning Mem. (Cold Spring Harbor, N.Y.) 18, 605-609).
One important molecular mediator for these beneficial responses in the brain to exercise is the induction of neurotrophins/growth factors, most notably brain-derived neurotrophic factor (BDNF). In animal models, BDNF is induced in various regions of the brain with exercise and most robustly in the hippocampus (Cotman et al. (2007) Trends Neurosci. 30, 464-472). BDNF promotes many aspects of brain development including neuronal cell survival, differentiation, migration, dendritic arborization, synaptogenesis and plasticity (Greenberg et al. (2009) J. Neurosci. 29, 12764-12767 and Park and Poo (2013) Nat. Rev. Neurosci. 14, 7-23). In addition, BDNF is essential for synaptic plasticity, hippocampal function and learning (Kuípers et al. (2006) Curr. Opin. Drug Disc. Dev. 9, 580-586). Highlighting the relevance of BDNF in human, individuals carrying the Val66Met mutation in the BDNF gene, exhibit decreased secretion of BDNF, display a decreased volume of specific brain regions, deficits in episodic memory function as well as increased anxiety and depression (Egan et al. (2003) Cell 112, 257-269 and Haríri et al. (2003) J. Neurosci. 23, 6690-6694). Blocking BDNF signaling with anti-TrkB antibodies attenuates the exercise-induced improvement of acquisition and retention in a spatial learning task, as well as the exercise-induced expression of synaptic proteins (Vaynman et al. (2004) Eur. J. Neurosci. 20, 2580-2590 and Vaynman et al. (2006) Brain Res. 1070, 124-130). However, the underlying mechanism which induces BDNF in exercise remains to be determined.
PGC-1α is induced in skeletal muscle with exercise and is a major mediator of the beneficial effects of exercise in this tissue (Finck and Kelly (2006) J. Clin. Invest. 116, 615-622). PGC-1α was initially discovered as a transcriptional co-activator of mitochondrial biogenesis and oxidative metabolism in brown fat (Puigserver et al. (1998) Cell 92, 829-839 and Spiegelman (2007) Novartis Foundation Sympos. 287, 60-69). Subsequent work has demonstrated an important role of PGC-1α in the brain. Lack of PGC-1α in the brain is associated with neurodegeneration (Lin et al. (2004) Cell 119, 121-135 and Ma et al. (2010) J. Biol. Chem. 285, 39087-39095), as well as GABAergic dysfunction and a deficiency in neuronal parvalbumin expression (Lucas et al. (2010) J. Neurosci. 30, 7227-7235). PGC-1α has been shown to be neuroprotective in the MPTP mouse model of Parkinson's disease (St-Pierre et al. (2006) Cell 127, 397-408). It also negatively regulates extrasynaptic NMDA (N-methyl-D-aspartate) receptor activity and thereby reduces excitotoxicity in rat cortical neurons (Puddifoot et al. (2012) J. Neurosci. 32, 6995-7000). In addition, the involvement of PGC-1α in the formation and maintenance of neuronal dendritic spines has been reported by Cheng et al. (2012) Nature Comm. 3, 1250 and long-term forced treadmill running over 12 weeks increases Pgc1α expression in various areas of the brain (Steiner et al. (2011) J. Appl. Physiol, 111, 1066-1071).
It has been determined that a PGC-1α-dependent myokine, FNDC5, is cleaved and secreted from muscle during exercise and induces some major metabolic benefits of exercise (Bostrom et al. (2012) Nature 481, 463-468). FNDC5 is a glycosylated type I membrane protein and is released into the circulation after proteolytic cleavage. The secreted form of FNDC5 contains 112 amino acids and has been named irisin. Irisin acts preferentially on the subcutaneous ‘beige’ fat and causes it to ‘brown’ by increasing the expression of UCP-1 and other thermogenic genes (Bostrom et al. (2012) Nature 481, 463-468 and Wu et al. (2012) Cell 150, 366-376). Clinical studies in humans have confirmed this positive correlation between increased FNDC5 expression and circulating irisin with the level of exercise performance (Huh et al. (2012) Metabolism 61, 1725-1738 and Lecker et al. (2012) Circ. Heart Failure 5, 812-818).
FNDC5 is also expressed in the brain (Dun et al. (2013) Neurosci. 240, 155-162; Ferrer-Martinez et al. (2002) Dev. Dyn. 224, 154-167; and Teufel et al. (2002) Gene 297, 79-83) and in rat pheochromocytoma-derived PC12 cells differentiated into neuron-like cells (Ostadsharif et al. (2011) Diff. Res. Biol. Diversity 81, 127-132). Knockdown of FNDC5 in neuronal precursors impaired the development into mature neurons (Hashemi et al. (2013) Neurosci. 231, 296-304) and in vitro application of irisin to mouse H19-7 HN hippocampal cells increased cell proliferation without altering markers of hippocampal neurogenesis (Moon et al. (2013) Metabolism 62:1131-1136).
Despite the identification of BDNF and other neuromodulatory (e.g., neuroprotective) factors as important regulators of neuronal development and function, such molecules are unstable, difficult to administer to the central nervous system, and are non-specific, general molecules having a range of functions on different parts of the central and peripheral nervous systems. A major part of the pathology of neurodegenerative disease is the progressive destruction and loss of neurons followed by loss of neurological function. Therapeutic efforts have concentrated on the protection and preservation of the endangered neurons as well as regeneration of new neurons. While neurotrophins, which are neuroprotective, promote nerve cell growth and survival, and have been become prime candidates because of their major therapeutic effects in animal studies, clinical trials using neurotrophins themselves as therapeutics have not been successful thus far for the reasons described above. Yet, there is a growing need for such therapeutics. Impairment of the nervous system caused by neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease, and the associated disability is devastating for the people suffering from it. In the United States at least one million people are believed to suffer from Parkinson's disease and about 60,000 people are newly diagnosed each year. The annual costs alone for Parkinson's disease are estimated at $25 billion per year in the U.S., including the cost of treatment, social security payments and lost income from inability to work.
Accordingly, there is a great need to identify molecular regulators of such neuromodulatory (e.g., neuroprotective) factors having improved properties for administration, neuromodulatory specificity, and stability, including the generation of diagnostic, prognostic, and therapeutic agents to effectively regulate neurological processes in subjects.